Project Summary Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. The disease has a relatively fast progression, with an average survival time of three years from diagnosis. Currently available therapeutic approaches are mostly focused on symptomatic interventions and results only in minor improvement in disease progression compared to controls. Therefore, new approaches are warranted. A vast majority of ALS-linked mutations are found in proteins that play vital roles in ribostasis and are major components of stress granules. These proteins play key roles in stress granule formation-dissolution according to cellular needs. Prior studies have demonstrated that prolonged presence of stress granules can be detrimental. Interestingly, mutations in these ALS-linked proteins often lead to increased stress granule persistence and reduce their fluid-like properties. Recent observations suggest that many of the ALS-linked proteins have prion-like domains and undergo liquid-liquid phase separation into dense, protein-rich droplets. These droplets can undergo aging and morph into tangle-like/starburst-like structures that bear surprising resemblance with neuropathologic lesions. The current study aims to identify drugs that prevent protein droplet aging without impacting droplet formation. This approach targets the ribonucleoprotein pathogenesis pathway that is nearly universal in ALS pathology, without perturbing the physiologically relevant liquid-liquid phase separation. Approximately 97% of ALS patients have ribonucleoprotein inclusion bodies that are assumed to be directly linked with disease. Loss of neurological function (and subsequent motor functions) impact patient?s quality of life significantly. An inhibition/prevention of pathogenic aggregation will prevent loss of neuronal functions and improve quality of life. Additionally, such interventions are expected to slow down disease progression significantly. It should be noted that currently available ALS drugs show only modest effects on prognosis and patient quality of life. Additionally, identified positive hits can lead to prophylactic drugs for individuals with high-susceptibility (genetic testing/family history based). The study will utilize libraries of currently approved drugs. This will vastly reduce the bench- to-bedside time, if drugs show positive results.